Prostate cancer (CaP) is the most common non-cutaneous malignancy in men and remains the second most common cause of male cancer deaths in North America. More than 90% of approximately 260,000 incident cases in North America present as localized disease. The prognosis of these cancers is stratified based on relative prostate-cancer specific mortality (PCSM) (e.g. low, intermediate and high-risk groups with hazard ratios for PCSM of approximately 1, 5 and 14, respectively) (D'Amico et al., 2003). These groupings are based on the levels of pre-treatment prostate-specific antigen (PSA), biopsy-based pathologic Gleason scores and UICC-TNM local and systemic staging descriptors. Many low risk patients can be offered active surveillance, sparing them the toxicities of radical treatment. High-risk patients often receive both local and systemic treatment in intensified protocols using radical prostatectomy (RadP) and/or image-guided radiotherapy (IGRT) combined with adjuvant androgen deprivation therapy (ADT) to offset the adverse impact of local failure and systemic occult metastases.
In contrast, the optimal treatment of the close to 75,000 North American men who present with non-indolent, intermediate-risk disease (e.g. highly similar Gleason scores of 6 or 7, PSA under 20 ng/mL and T1-T2N0M0) is an ongoing clinical dilemma (Shao et al., 2009). Up to one third of these patients undergo biochemical relapse, despite attempts at curative treatment using precision RadP or IGRT (Nichol, Warde, & Bristow, 2005). Furthermore, up to 12,000 (18%) of these patients fail within 18 months of primary therapy, and this heralds occult metastatic disease and increased PCSM (Buyyounouski, Pickles, Kestin, Allison, & Williams, 2012; Freedland et al., 2005; Johnson et al., 2013; Kapadia, Olson, Sandler, Feng, & Hamstra, 2012) As such, despite the use of clinical prognostic factors, intra- and inter-patient heterogeneity leads to clinical imprecision in the determination of which patients need treatment intensification a priori with ADT, chemotherapy or targeted therapies in order to prevent lethal castrate-resistant disease.
At present, no treatment-independent (e.g. useful for both IGRT and RadP patients), genome-wide signature exists to classify patients as potential responders or non-responders derived from initial diagnostic treatment biopsies. A pre-treatment, biopsy-based genomic signature reflecting tumour aggression could triage patients to intensified therapies and justify the additional toxicity to achieve cure in patient subgroups that are currently incurable by local therapy alone. Gene-specific studies have shown that copy number alterations (CNAs) in pre-treatment biopsies of PTEN, NKX3-1, MYC and the AR can associate with adverse prognosis in intermediate risk patients (Locke, Zafarana, Ishkanian, et al., 2012; Locke, Zafarana, Malloff, et al., 2012; Shen & Abate-shen, 2010; Zafarana et al., 2012). RNA-based gene signatures derived based on trans-urethral resections (TURP) or post-radical prostatectomy specimens (e.g. post-treatment) have been published which may differentiate between indolent and non-indolent prostate cancers ((J Cuzick et al., 2012; Jack Cuzick et al., 2011; Markert, Mizuno, Vazquez, & Levine, 2011; Penney et al., 2011; Wu et al., 2013). Surprisingly, and perhaps disappointingly, TMPRSS2:ERG fusion status is not associated with altered prognosis after either RadP (Minner et al., 2011) or IGRT (Dal Pra et al., 2013)). Finally, tumour cells do not exist within a homogenous microenvironment and intratumoural hypoxia has been linked to increased genetic instability, decreased DNA repair, decreased capacity for apoptosis, increased stress adaption including augmented autophagy, increased angiogenesis and increased metastatic potential (Bristow & Hill, 2008; Wouters & Koritzinsky, 2008). Indeed, prostate cancers harbouring hypoxic sub-regions are also aggressive and fail within the first 2 years (early failure) following IGRT or RadP (Milosevic et al., 2012; Turaka et al., 2012; Vergis et al., 2008). To date, there has not been any investigation or exploration of the potential interplay between genomic instability and hypoxia in the same tumour within the context of treatment outcome.
Low and intermediate risk cancers can be distinctly classified into subgroups based on their significant inter-patient genetic and microenvironmental heterogeneity in which some patients are extremely unlikely to fail therapy and others fail rapidly within 2 years of therapy. These translational outcome data, when combined with research findings that show that disparate CNA prognostic signatures can exist within foci of similar Gleason score (Boutros et al., 2013; Cooper, 2013), together sets the stage for aggressive ascertainment of both genomic and microenvironmental data prior to therapy. These novel combinatorial indices can be used to offer patients medical intensification and de-intensification strategies in the context of precision cancer medicine (Chin, Andersen, & Futreal, 2011; Tran et al., 2012).